Deficiency in Inhibitory Cortical Interneurons Associates with Hyperactivity in Fibroblast Growth Factor Receptor 1 Mutant Mice

• Published in: Biological psychiatry (1969) 2008-05, Vol.63 (10), p.953-962
• Main Authors: Smith, Karen Müller, Fagel, Devon M, Stevens, Hanna E, Rabenstein, Rebecca L, Maragnoli, Maria Elisabetta, Ohkubo, Yasushi, Picciotto, Marina R, Schwartz, Michael L, Vaccarino, Flora M
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Amphetamine - therapeutic use; Animals; Behavior, Animal - drug effects; Biogenic Monoamines - metabolism; Biological and medical sciences; Cell Count - methods; Central Nervous System Stimulants - therapeutic use; Cerebral Cortex - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Dopamine Agents - administration & dosage; Exploratory Behavior - drug effects; Fgf; Fibroblast Growth Factor 1 - deficiency; Fibroblast Growth Factor 1 - genetics; GAD67; Glutamate Decarboxylase - metabolism; hyperactivity; Hyperkinesis - drug therapy; Hyperkinesis - genetics; Hyperkinesis - pathology; Locomotion - drug effects; Locomotion - genetics; Male; Medical sciences; Methylphenidate - therapeutic use; Mice; Mice, Knockout; Motor Activity - drug effects; Motor Activity - genetics; Nerve Tissue Proteins - metabolism; Neural Inhibition - genetics; Neurology; Neurons - pathology; Organic mental disorders. Neuropsychology; parvalbumin; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Schizophrenia; Signal Transduction - drug effects; Signal Transduction - genetics; Tourette Syndrome
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2007.09.020

Background Motor hyperactivity due to hyper-dopaminergic neurotransmission in the basal ganglia is well characterized; much less is known about the role of the neocortex in controlling motor behavior. Methods Locomotor behavior and motor, associative, and spatial learning were examined in mice with conditional null mutations of fibroblast growth factor receptor 1 (Fgfr1) restricted to telencephalic neural precursors ( Fgfr1f/f;hGfapCre ). Locomotor responses to a dopamine agonist (Amphetamine 2 mg/kg and Methylphenidate 10 mg/kg) and antagonists (SCH233390 .025 mg/kg and Haloperidol .2 mg/kg) were assessed. Stereological and morphological characterization of various monoaminergic, excitatory, and inhibitory neuronal subtypes was performed. Results Fgfr1f/f;hGfapCre mice have spontaneous locomotor hyperactivity characterized by longer bouts of locomotion and fewer resting points that is significantly reduced by the D1 and D2 receptor antagonists. No differences in dopamine transporter, tyrosine hydroxylase, or serotonin immunostaining were observed in Fgfr1f/f;hGfapCre mice. There was no change in cortical pyramidal neurons, but parvalbumin+, somatostatin+, and calbindin+ inhibitory interneurons were reduced in number in the cerebral cortex. The decrease in parvalbumin+ interneurons in cortex correlated with the extent of hyperactivity. Conclusions Dysfunction in specific inhibitory cortical circuits might account for deficits in behavioral control, providing insights into the neurobiology of psychiatric disorders.